Action Points

Be aware that this was a study performed in a single center, and will need to be validated in other cohorts before clinical use becomes routine.

Pediatric stem-cell recipients had significantly better survival and a reduced risk of disease progression when matched with donors who had a specific natural killer (NK)-cell protein, investigators reported.

The results add to laboratory evidence that NK cells expressing KIR2DL1 had increased activity against cancer cells, reported Wing Leung, MD, PhD, of St. Jude Children's Research Hospital in Memphis, Tenn., and colleagues online in the Journal of Clinical Oncology.

"This approach should dramatically improve the outcome of patients undergoing bone marrow transplantation, regardless of their age or underlying condition," Leung said in a statement. "NK cells also play an important role in autoimmune disorders, chronic infections, and other conditions, so these results will likely have an impact beyond cancer."

Improving Donor Selection

Clinical application of hematopoietic stem cell transplantation (HSCT) has increased and offers a potential cure for a variety of malignancies, genetic diseases, and other disorders. Despite advances in transplantation science, matching between donor and recipient remains critical to success. Investigators in several laboratories have explored potential markers that could improve donor selection beyond HLA matching.

Routine typing of KIRs has been proposed as a means to improve donor selection, the authors noted. KIRs reside on the surface of NK cells and certain cytotoxic T cells. Recent clinical studies have shown that inhibitory and activating KIRs play a role in the success of HSCT for malignant and nonmalignant conditions.

To date, 15 members of the KIR family have been identified, including KIR2DL1, which is found in 90% to 95% of healthy individuals. KIR2DL1 inhibits NK cell activity and "educates" NK cells in recognizing ligand group 2 HLA-CLys80 (C2).

Some studies have suggested that the presence of donor KIR2DL1 and absence of recipient C2 (receptor-ligand mismatch) predict more favorable outcomes, but results from different transplantation centers have been inconsistent, the authors continued.

Recently, Leung and colleagues reported that KIR2DL1 alleles with arginine in position 245 of the transmembrane domain (KIR2DL1-R245) are stronger than those with cysteine (KIR2DL1-C245). Continuing that line of research, investigators examined the influence of donor KIR2DL1-R245 and KIR2DL1-C245 on outcomes after allogeneic HSCT.

The authors performed allotyping for KIR2DL1 using DNA samples from donors for 313 patients who underwent allogeneic HSCT at St. Jude from January 2000 to January 2010. The patients had a median age of 9.9 years at transplantation, and indications for HSCT were hematologic malignancies in 231 cases, solid tumors in 25, and nonmalignant conditions in 57.

Among the 256 patients with malignancies, 143 (56%) were in remission at the time of transplantation and the rest had persistent disease. Of the entire study population, 175 (56%) patients received conditioning regimens that included total-body irradiation, which was myeloablative in 76% of cases.

Donors were matched siblings in 27% of cases, matched unrelated donors in 31%, and haploidentical donors in 41%.

The authors found that 215 of 313 donors were homozygous for KIR2DL1-R245, 22 were homozygous for KIR2DL1-C245, and 76 were heterozygous.

Recipients of KIR2DL1-R245 had a significantly lower hazard for death after transplantation as compared with recipients of stem cells from homozygous KIR2DL1-C245 donors (hazard ratio 0.4, 95% CI 0.25-0.64, P=0.0001), as did patients who received stem cells from heterozygous donors (HR 0.42, 95% CI 0.25-0.71, P=0.0013).

Survival did not differ between patients who received homozygous KIR2DL1-R245 stem cells and those who received stem cells from heterozygous donors.

Limiting the analysis to the 231 patients with hematologic malignancies, Leung and colleagues found that patients who received stem cells from homozygous or heterozygous KIR2DL1-R245 donors still fared significantly better than those patients who received stem cells from homozygous KIR2DL1-C245 donors (P=0.0007).

Similar results emerged from analyses of specific types of hematologic malignancies and analyses of sibling donors, unrelated donors, and haploidentical donors.

An analysis limited to patients with hematologic malignancies yielded similar results, as did an analysis by type of hematologic malignancy.

Are the Results Enough to Move Forward?

The test for KIR2DL1 is available at most clinical laboratories, and the allotyping can be performed at the same time as HLA matching of a donor sample, according to Anna Pawlowska, MD, of City of Hope in Duarte, Calif.

"Based on these impressive results, I think KIR testing should be performed and reviewed at the time of donor selection and included with other factors when choosing a donor," Pawlowska said via email. "KIR testing using the current method has been done at City of Hope since 2005."

The results are intriguing but require validation in a well-designed prospective study, said Edward Copelan, MD, of Carolinas Healthcare System's Levine Cancer Institute in Charlotte, N.C.

"Typing was performed retrospectively at a single institution in pediatric patients," Copelan, who was not involved in the study, told MedPage Today by email. "The patient population is heterogeneous with regard to underlying disease, disease stage, transplant preparative regimen, donor type, and the use of T-cell depletion, complicating multivariate analysis."

"Many of the subset analyses were performed in small numbers of patients, and larger numbers of patients are needed for proper analysis of these specific situations," Copelan added. "In contrast to this study, many studies of KIR effect on relapse have shown an effect in acute meyloid leukemia but not in acute lymphoblastic leukemia.

"Lastly, it is unclear whether these results in pediatric patients are applicable to adults."

The study was supported by the NIH.

Leung and co-authors reported no conflicts of interest.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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